Background C-C chemokine receptor 1 (CCR1) and its ligands are overexpressed in synovial tissue and fluid suggesting a role in rheumatoid arthritis (RA). Early clinical studies hinted that CCR1 inhibition may be clinically efficacious. A highly selective CCR1 antagonist (BMS-817399) with high functional potency (IC₅₀ ∼30 nM) against multiple CCR1 ligands and a favorable Phase I clinical safety profile was investigated in a proof-of-concept study in patients with RA.

Objectives To test BMS-817399 clinical efficacy in RA patients based on DAS28-CRP change from baseline, and proportion of ACR 20, 50 and 70 responses at 12 weeks. Safety, pharmacokinetics and pharmacodynamics were also evaluated.

Methods A Phase 2, double blind, placebo controlled clinical trial was conducted in 123 patients with moderate to severe RA (≥6 SCJ and ≥6 TJC in 28 joint count) with inadequate response to MTX (≥10 mg/week, stable for ≥6 weeks) and elevated CRP (>3mg/L). Patients were randomized 1:1:1 to placebo, 200 mg BID, or 400 mg BID on stable background MTX. The most swollen hand/wrist was imaged at baseline and Week 12 using 1.5T magnetic resonance imaging (MRI) with contrast enhancement.

Results Demographic characteristics and disease activity were similar across treatment groups at baseline. The adjusted mean change (SE) from baseline in DAS28-CRP at 12 weeks was -1.20 (0.18), -1.04 (0.19) and -1.03 (0.19) in the placebo, 200 mg BID and 400 mg BID groups, respectively (adjusted for baseline disease activity and prior use of biologic DMARDs). Similarly, the proportion of ACR 20, 50 and 70 responders at 12 weeks was similar across the treatment groups, independent of prior use of biologic DMARDs. No differences were seen in any of the MRI RAMRIS components at Week 12. BMS 817399 mean trough concentrations (Cmin) at Day 15 reached steady-state and the ratios of Cmin to the ex vivo functional IC₉₀ for MIP-1α were ∼17 and 46 for the 200 and 400 mg BID groups, respectively. Increased concentrations of ligands (MIP-1α and MIP-1β) in the serum of only BMS-817339-treated groups confirmed target engagement. Overall, BMS-817399 was safe and well-tolerated and most adverse events (AEs) were mild. No serious infections were reported in the study.

Conclusions Overall, BMS-817399 was safe and well-tolerated but showed no evidence of clinical efficacy in RA patients with moderate to severe disease activity with inadequate response to MTX. No MRI improvements on synovitis or osteitis were induced by BMS-817399. Furthermore, the in vivo biologically effective CCR1 inhibition was confirmed by the selective increase of ligands only in the 2 treated arms and BMS-817399 exposures in both treated groups were at least 17x above IC₉₀ for MIP-1α, minimizing a lack of efficacy caused by insufficient exposure or transitory target engagement. This study strongly indicates that in vivo biologically effective CCR1 inhibition does not provide clinical benefits in moderate to severe RA patients.

Disclosure of Interest : A. Kivitz Grant/research support: Bristol-Myers Squibb, Speakers bureau: Bristol-Myers Squibb, P. Maciag Shareholder of: Bristol-Myers Squibb, P. Gulati Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, S. Du Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, S. Connolly Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, P. Davies Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, X. Li Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, T. Repsher Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, H. Haggerty Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, M. Londei Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb

DOI 10.1136/annrheumdis-2014-eular.3871